Presentation on theme: "Advanced Organic Chemistry"— Presentation transcript:
1 Advanced Organic Chemistry Part B: Reactions and Synthesis4th EditionFrancis A. Carey and Richard J. SundbergKluar Academic / Plenum Publishers
2 Chapter 1. Alkylation of Nucleophilic Carbon Intermediates IntroductionC-C bond formation is the basis for the construction of the molecular frame work of organic molecules by synthesis.One of fundamental processes for C-C bond formation is a reaction between a nucleophilic carbon and an electrophilic one.Reaction of C-nucleophile (enolate ions, imine anions, enamines) with alkylating agents
3 Crucial Factor for C-C bond formation by SN2 reaction (1) the condition for generation of the carbon nucleophile(2) the effect of the reaction conditions on the structure and reactivity of the nucleophile(3) the regio- and stereoselectivity of the alkylation reaction(4) the role of solvent, counterions, and other components of the reaction media that can influence the rate of competing reactions
4 1.1 Generation of Carbanions by Deprotonation The rate of deprotonation and the stability of the resulting carbanion are enhanced by the presence of substituent groups that can stabilize negative charge.Several typical examples of proton abstraction equilibria is shown in scheme 1.1
8 Favorable equilibrium between a carbon acid and its carbanion will be established if the base which is used appears below the acid in the table 1.1An ordering of some important substituents with respect to their ability to stabilize carbanion can be established.NO2> COR>CN-CO2R>SOR>Ph-SR>H>R
9 Strong base, but it is sufficiently bulky so as to be relatively nonnucleophilic. Lithium, sodium, potassium of hexamethyldisilazane, [(CH3)2Si]2NHAprotic solvent: ether, tetrahydrofurane (THF), dimethoxyethane (DME)
10 1.2 Regioselectivity and Stereoselectivity in Enolate Formation
11 Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative, and irreversible.Lithium is better counterion than sodium or potassium for regioselectivegeneration of the kinetic enolate, since lithium maintains a tighter coordinationat oxygen and reduces the rate of proton exchange.
12 Aprotic solvents are essential because protic solvents permit enolate equilibrium by reversible protonation-deprotonation,which gives rise to the thermodynamically controlled enolatecomposition. Excess ketone also catalyzesthe eqiulibriationby proton exchange.Conditions of kinetic control usually favor the less substitutedenolate.At equilibrium, thermodynamic controlled conditions, the moresubstituted enolate is usually the dominat species.
26 Dilithium derivatives of acetoacetic acid is also a synthetic equivalent of acetone enolate. Hydrolysis step is unnecessary, and decarboxylation canbe done directly.Alkylation also can be carried out using silyl enol ethers by reaction withfluoride ion such as tetraalkylammonium fluoride salts.
29 Little steric difference between two faces, upper and lower faces. transcis1/1 ratio of the prducts
30 Pseudoaxial conformation because of allylic strain The upper face of the enolate presents three hydrogens in a 1,3-diaxialrelationship to the approaching electrophile. (lower face are equatorial)
31 Axial attack from the lower face leads directly to the chair conformation of the product.1,3-diaxial interation with the approaching electrophile.A strong preference for alkylation to give the cis ring junction
32 According to molecular mechanicsm the minimum-energy conformation of the enolate is a twist-boat conformationIntramolecular ring-closure reactionJ is more favorable than K due to the ring strain
33 1.5 Generation and Alkylation of Dianions Second deprotonationRef. Scheme 1.8First deprotonation1.6 Medium Effect in the Alkylation of EnolatesDMF and DMSO are effective in enhancing the reactivity of enolate anions,polar aprotic solvent.
35 Polar aprotic solvents possess excellent metal-cation coordination ability,so they can solvate and dissociates and other carbaions from ion pairs andclusters.Polar aprotic solvents are good cation solvators and poor anion solvators.
36 Polar protic solvents coordinate to both the metal cation and the enolate ion. Water, alcohol, or ammoniaPolar protic solvents are less reactive than the same enolate in a polaraprotic solvent such as DMSO.Despite the somewhat reduced reactivity of aggregated enolates, THF andDMF are the most commonly used solvents for the synthetic reactionsinvolving (kinetic) enolate alkylation.Enolate can be enhanced by adding a reagent that can bind a alkali-metalCations: HMPA, tetramethylenediamine(TMEDA), crown ethers.12-crown-4; Li, 18-crown-6; Na, K.Mg2+ < Li+ < Na+ < K+ : reactivity order of enolate; the smaller, the harderstrongly bind to oxygen
37 1.7 Oxygen versus Carbon as the Site of Alkylation Enolate anions are ambient nucleophile.O-alkylation, when the enolate is dissociated.
38 Leaving-group effects on the C- or O-alkylation: hard-soft-acid-base(HSAB) Oxygen is harder than carbon.Oxygen leaving group such as sulfonate and sulfate are harder: reacts atthe hard oxygen site of the enolate.The amount of O-alkylation is amximized by use of an alkyl sulfate or alkylsulfonate in a polar aprotic solvent. And that of C-alkylation is maximizedby an alkyl halide in a less polar solvent such as THF or DME.
39 With 5-membered rings, colinearity cannot be achieved easily. The transition state for O-alkylation involves an oxygen lone-pair orbitaland is less strained than the transition state for C-alkylation.
40 The kinetically preffered site for both protonation and alkylation is the a-carbon The a carbon has a great negative charge compared with g carbon.
41 Strong preference for O-alkylation in Phenoxide ions because C-alkylation disrupts aromatic conjugationPhenoxides undergo O-alkylation in solvent such as DMSO, DMF,ethers, and alcohols. However, in water and trifluoroethanol, extensiveC-alkylation occurs.
42 1.8 Alkylation of Aldehyde , Esters, Amides, and Nitriles Alkylation of aldehyde enolate is not very common because of facileadol condensation by base. But rapid, quantitative formation of enolateavoids this: KNH2 in NH3, KH in THF.Alkylation of simple esters requires a strong base: weak base such as alkoxidepromotes condensation reaction. Strong base: LDA, hesamethyldisilylamide(KHMDS). Ref. Scheme 1.9
48 1.9 The Nitrogen Analogs of Enols and Enolates-Enamines and Imine Anions Imine is the nitrogen analog of ketone and aldehyde.Removed byazeotropicdistillationFor secondary amine, vinylamine or enamine is formed.Strong dehydrating reagents to drive the reaction to completion: TiCl4 orTriethoxysilane. N-Timethylsilyl derivative: strong affinity of silicone foroxygen than nitrogen.
49 The b-carbon atom of an enamine is a nucleophilic site because of conjugation With the nitrogen atom.Alkylation of enamine
50 Pyrrolidine enaminePreferred enamineA serious nonbonded repulsion (A1,3 strain) destabilizes isomer 7.Because of the predominance of the less substituted enamine, alkylationoccur primarily at the less substituted a carbon.trans
51 Imine can be deprotonated at the carbon by strong base to give the nitrogen analog of enolates: imine anions or metalloenamines.Isoelectronic and structurally analogous to both enolaes and allyl anions andcan also be called azaallyl anions.In toluene it exists as dimeric form, but at high THF concentration, the monomerIs favored.
53 Just as enamines are more nucleophilic than enols, imine anions are more nucleophilic than enolates and react efficiently with alkyl halides.
54 The nitrogen substituent R’ is syn to the double bond are the more stable.
55 Lithiated ketimines room temperature: thermodynamic composition is established. less substituted isomer: the most stable structure.Table 1.3 entry 2 : a) chelation of the methoxy group with the lithium ionb) The interaction of the lithium with the bromidec) the steric effect of the benzyl group
65 Hindered Aluminum tris(2,6-diphenylphenoxide) is an effective promoter. Ketone enolates react with enone to give 1,5-diketones.ref scheme 1.12Quaternary carbon atom centers are easily generated. (kinetically controlledenolate)
68 Z-enolate favors anti-adduct and E-enolate favors syn-adduct. Chelated transition state
69 The stereoselectivity can be enhanced by addition of Ti(O-i-Pr)4. Much larger Ti(O-i-Pr)4 group replaces Li+.
70 When the conjugate addition is carried out under kinetic conditions with stoichiometric formation of the enolate, the adduct is also an enolate untilthe reaction is quenched with a proton source. Tandem reaction is possible.
71 Tandem conjugate addition reaction is an efficient means of introducing both a and b substituents at enones.Trimethylsilyl enol ether can be used with TiCl4.-78oC
72 The initial adduct is trapped in cyclic form by trimethylsilylation. Other Lewis acidLanthanide salts catalyze addition of a-nitroesters evenin aqueous solution.
73 Alcoholic solution of potassium or sodium cyanide Triethylaluminum-hydrogen cyanide and diethylaluminum cyanideMore reactiveAluminum reagent might act as a Lewis acid at the carbonyl center
74 With chiral oxazoline, 30-50% diastereomeric excess (d. e With chiral oxazoline, 30-50% diastereomeric excess (d.e.) can be achieved.
75 The addition of enamines of cyclohexanones show a strong preference for attack from the axial direction, because the pi-orbital of the enamineis the site of nucleophilicity.
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